Dissecting the role of endosomal Toll-like receptors in PSP and CBD

Pathway Grant

Principal Investigator: Dr. Steven Boeynaems, Baylor College of Medicine

As implied by their name, neurodegenerative diseases arise from the loss of neurons. While these cells may claim the spotlight, other cell populations in the brain also contribute to these diseases. Microglia and astrocytes transition into a hyperinflammatory state, further straining the already sick neurons. Additionally, oligodendrocytes, which regulate proper neuronal signal transduction, degenerate as well. The dysfunction of all of these neuronal support cells wreaks havoc on the brain and its proper functioning. This is also the case in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD).

Intriguingly, it seems that the dysfunction of these cells emerges from their aberrant inflammation. All these support cells are able to sense invading pathogens, like bacteria or viruses, and in disease they just seem to do so. But why these cells act as if the brain is fighting off an infection remains incompletely resolved. Since neuroinflammation is a critical modifier of disease progression in animal models and patients, understanding the molecular origins of this aberrant inflammation may hold promising leads for therapeutic intervention.

In this project, we propose the provocative idea that the abnormal toxic protein aggregates that pile up in PSP and CBD trick the brain's cellular immune system into thinking there is an ongoing bacterial infection. Moreover, we identified the molecular antennae that get stimulated on these cells, triggering their toxic hyperactivation. By further investigating the details of the complex molecular signals that lead up to this, we hope to identify therapeutic strategies that block these antennae and their signal transmission. In all, we propose that helping neuronal support cells to calm down will provide a better environment for the neurons to survive and could slow down the progression of these diseases.